Novel Chimeric Histone Deacetylase Inhibitors: A Series of Lapatinib Hybrides as Potent Inhibitors of Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and Histone Deacetylase Activity

Abstract

Reversible lysine-specific acetylation has been described as an important posttranslational modification, regulating chromatin structure and transcriptional activity in the case of core histone proteins. Histone deacetylases (HDAC) are considered as a promising target for anticancer drug development, with 2a as pan-HDAC inhibitor approved for cutanous T-cell lymphoma therapy and several other HDAC inhibitors currently in preclinical and clinical development. Protein kinases are a well-established target for cancer therapy with the EGFR/HER2 inhibitor 5 approved for treatment of advanced, HER2 positive breast cancer as a prominent example. In the present report, we present a novel strategy for cancer drug development by combination of EGFR/HER2 kinase and HDAC inhibitory activity in one molecule. By combining the structural features of 5 with an (E)-3-(aryl)-N-hydroxyacrylamide motif known from HDAC inhibitors like 1 or 3, we obtained selective inhibitors for both targets with potent cellular activity (target inhibition and cytotoxicity) of selected compounds 6a and 6c. By combining two distinct pharmacologically properties in one molecule, we postulate a broader activity spectrum and less likelihood of drug resistance in cancer patients.

Trastuzumab enhances the anti-tumor effects of the histone deacetylase inhibitor sodium butyrate on a HER2-overexpressing breast cancer cell line

“…Kip1 levels and the cyclinE-Cdk2 complex binding (14)(15)(16)(17). Trastuzumab also blocks the HER2 downstream signaling to influence the cell cycle and apoptosis (10).…”

Perspectives in the development of hybrid bifunctional antitumour agents

“…Indeed, some multi-kinase inhibitors have been reported to be effective for receptor tyrosine kinases (RTK) of the EGFR family, c-Met/VEGFR or protein kinases PI3K/mTOR. Initial efforts to combine the pharmacological properties of multitarget inhibitors have been reported in two independent studies in which chimeric molecules were designed as inhibitors of EGFR, HER2 and HDAC activity [32,33]. CUDC-101 (13), [33] displayed a potent antiproliferative and antitumour activity against a number of tumour models, including lapatinib-and erlotinibresistant tumour cell lines.…”

Histone deacetylase inhibitors merged with protein tyrosine kinase inhibitors

“…On the contrary, even though bioisosteres, vinylogous and substitution patterns had nothing to do with EGFR/Her2 inhibition, compared to laptinib, each compound showed expectant ability for inhibiting EGFR/Her2. In addition, they also investigated cytotoxicity of these compounds towards some selected cancer cell lines and found that 25a and 25c were the most potential chimeric inhibitors (37). From these preclinical data, some improvements could be seen noticeably, but HDAC inhibition activity was far from satisfactory.…”